A key treatment for diabetic macular oedema (DMO) is ranibizumab (Lucentis®), which is approved at differing doses: 0.5 mg/month in Europe and 0.3 mg/month in the US. The relative efficacy and safety of these doses, however, is a controversial issue. A wide ranging literature search was conducted to examine the evidence supporting these doses. The searches identified only four studies that evaluated the 0.3 mg ranibizumab dose, in which best-corrected visual acuity (BCVA) improvements ranged from +5.7 to +12.8 letters during treatment. The searches also identified 12 key studies that evaluated the 0.5 mg dose of ranibizumab, in which BCVA improvement ranged from +6.1 to +10.3 letters. The pivotal RIDE and RISE studies (n=382 and 377) were the only direct comparisons of the 0.3 mg and 0.5 mg ranibizumab doses and placebo. A pooled analysis of these studies showed that improvements in BCVA were numerically higher for the 0.3 mg-treated groups than for the 0.5 mg-treated groups at 24 and 36 months. Patients who were initially treated with sham injections and switched to ranibizumab did not match the improvements in those treated from the start. There was also little difference in central retinal thickness reduction between the two doses (261.8 and 261.2 μm versus 266.7 and 269.1 μm). Ranibizumab was well tolerated, adverse events occurred at similar frequencies in all groups, with a slightly greater incidence of stroke for the 0.5 mg dose. Analysis of RIDE and RISE also showed that ranibizumab is cost-effective. Overall, the data indicate that the 0.3 mg dose of ranibizumab is generally as effective as the 0.5 mg dose in DMO treatment.
Ranibizumab, diabetic macular oedema,cost-effectiveness
Jean-Francois Korobelnik has been a consultant for Alcon, Alimera, Allergan, Bayer, Horus, Novartis, Roche, Théa and Zeiss.
Compliance with Ethics Guidelines: This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.
Medical writing assistance was provided by James Gilbart, Touch Medical Media.
Authorship:All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.
September 14, 2016 Accepted
November 16, 2016
Jean-Francois Korobelnik, Department of Ophthalmology, CHU de Bordeaux, Hopital Pellegrin, Place Amélie Raba Léon, 33000 Bordeaux, France. E: firstname.lastname@example.org
This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.
Diabetic macular oedema (DMO) is an increasingly serious healthcare issue and a leading cause of blindness worldwide.1 Of the estimated 415 million people with diabetes globally, 7–12% have signs of DMO and 1–3% have visual impairment as a result.2,3 This burden affects populations in all territories and is likely to increase substantially when the prevalence of diabetes burgeons to a predicted 642 million by 2040.2–4 The availability of effective and tolerable treatments for the management of DMO is therefore critical in tackling a potential epidemic of blindness and visual impairment. Several treatments are available for DMO, including laser photocoagulation, intravitreal corticosteroids and anti-vascular endothelial growth factor (VEGF) agents. Prominent among the anti-VEGF agents is ranibizumab (Lucentis®, Genentech, California, US), which has an extensive body of clinical trial data supporting its efficacy and tolerability in DMO, and on which its approval by the US Food and Drug Administration and the European medicines Agency for use in this indication is based.5–10 This monoclonal antibody (MAb) treatment has been used successfully as monotherapy and in combination with laser photocoagulation and with other treatments.11–19 Manufacturing biological therapies, including MAbs, is an expensive process and their generally high cost has the potential to restrict usage in many territories, especially where healthcare resources are limited.20–22 Reducing the dose of MAbs could lower this cost, provided that efficacy is not compromised markedly. Currently the licensed dose for ranibizumab in DMO in Europe is 0.5 mg/month as an intravitreal injection. In the US, however, the licensed dose is 0.3 mg/month due to concerns of cardiovascular risks in diabetic patients. This article reports the findings of literature searches of clinical studies that investigated the comparative efficacy and safety and cost-effectiveness of the 0.5 mg dose of ranibizumab in DMO compared with the lower 0.3 mg dose. These searches aimed to identify if there was superior efficacy in terms of visual acuity (VA) and central retinal thickness (CRT) or safety for either dose level in DMO treatment and whether the lower dose could be used as an alternative in many cases and thereby reduce costs.
Literature search methods and results
Combined searches were made in BIOSIS Previews®, British Library Inside Conferences, Embase®, Embase® Alerts and MEDLINE®, with no date restriction. Title and abstract terms searched for included MeSH terms for clinical studies in DMO, or diabetic retinopathy restricted to ranibizumab and 0.5 mg or 0.3 mg. In total, 157 unique references were identified. After removal of irrelevant articles and duplicate reports of the same studies, 47 relevant studies were identified. Of these, four studies included groups given only 0.3 mg ranibizumab as a comparator or single therapy,
28 studies included groups given only 0.5 mg ranibizumab and only two studies directly compared the 0.3 mg and 0.5 mg ranibizumab doses. The designs, patient dispositions and findings of these categories are summarised in Tables 1, 2 and 3 (only completed studies with >40 patients for the ranibizumab 0.5 mg dose are tabulated).
The effect of different ranibizumab dosing regimens, the efficacy of ranibizumab compared with other treatments for DMO and in combination with other agents is outside the scope of this article.
Studies including only a 0.3 mg ranibizumab dose group – in diabetic macular oedema
There have been few studies that evaluated the 0.3 mg ranibizumab dose as a discrete group in the treatment of DMO (see Table 1). The four relevant studies ranged from 22 to 666 patients in size (mean 222 patients) and treatment durations varying from three months to two years.23–26 In three of the studies, ranibizumab monotherapy was a comparator against alflibercept, or bevacizumab or compared or in combination with AKB-9778 (a small-molecule competitive inhibitor of vascular endothelial-protein tyrosine phosphatase).23,25,26 One study was a retrospective chart review.24 Treatment durations were from one month to two years, during which best-correct visual acuity (BCVA) improved from +5.7 to +12.8 letters and improvements in VA. In one study there were no significant differences at the end of two years in VA for ranibizumab 0.3 mg compared with aflibercept 2.0 mg or bevacizumab 1.25 mg (p=0.18 for both) for patients with worse baseline VA (20/50 to 20/320).25 Results were similar in patients with better baseline VA (20/32 to 20/40). In another study ranibizumab 0.3 mg was significantly better than bevacizumab 1.25 mg in terms of VA -6.6 letters versus 5.3 letters (p=0.039).26 Reductions in CRT were -89 and -137 μm during treatment for bevacizumab and ranibizumab, respectively (p=<0.001). The ranibizumab treatment in these studies was well tolerated with no new adverse events profiles, i.e., these profiles being similar to those reported for the phase III studies.27,28
These studies had varying designs, study endpoints, patient populations and treatment durations, making direct comparisons difficult. However, a strong overall message that emerges from these studies is that 0.3 mg dose of ranibizumab is effective and has potential as a clinical treatment in DMO which was similar to or superior to that of some other treatments.
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Ranibizumab, diabetic macular oedema,cost-effectiveness